Glutamate transporters in brain ischemia: to modulate or not?

Abstract

In this review, we briefly describe glutamate (Glu) metabolism and its specific transports and receptors in the central nervous system (CNS). Thereafter, we focus on excitatory amino acid transporters, cystine/glutamate antiporters (system x c -) and vesicular glutamate transporters, specifically addressing their location and roles in CNS and the molecular mechanisms underlying the regulation of Glu transporters. We provide evidence from in vitro or in vivo studies concerning alterations in Glu transporter expression in response to hypoxia or ischemia, including limited human data that supports the role of Glu transporters in stroke patients. Moreover, the potential to induce brain tolerance to ischemia through modulation of the expression and/or activities of Glu transporters is also discussed. Finally we present strategies involving the application of ischemic preconditioning and pharmacological agents, eg β-lactam antibiotics, amitriptyline, riluzole and N-acetylcysteine, which result in the significant protection of nervous tissues against ischemia.

An electrochemiluminescent method for glutamate measurement in small microdialysate samples in asphyxiated young rats

“…This observation seems to be common in several previous reports, where it was observed that the high K + stimulus produces a rise in Glu content, but also falls while the stimulus is still present . Extracellular levels of Glu are controlled by four types of high‐affinity, sodium‐dependent glutamate transporters: GLAST and GLT‐1, localized primarily in astrocytes, EAAC1, widely distributed in neurons, and EAAT4 localized principally in cerebellar Purkinje cells . GLT‐1 is responsible for uptake up 90% of the total Glu, being a relevant factor the enzyme glutamine synthetase, which converts Glu into glutamine inside of astrocytes .…”

“…[43] Extracellular levels of Glu are controlled by four types of high-affinity, sodium-dependent glutamate transporters: GLAST and GLT-1, localized primarily in astrocytes, EAAC1, widely distributed in neurons, and EAAT4 localized principally in cerebellar Purkinje cells. [44] GLT-1 is responsible for uptake up 90% of the total Glu, [45] being a relevant factor the enzyme glutamine synthetase, which converts Glu into glutamine inside of astrocytes. [46] We (data not published) and others have observed astrogliosis as a long-term response before an early hypoxic event.…”

Chloride co‐transporters as possible therapeutic targets for stroke

“…; Krzyżanowska et al . ). NMDA receptors, which play an important role in synaptic development, and learning and memory, are found throughout the brain (Monyer et al .…”

“…Most studied neuroprotectants for the treatment of stroke have targeted the DL-a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor and the NMDA receptor, which are glutamate-activated ion channels (Besancon et al 2008;Krzy_ zanowska et al 2014). NMDA receptors, which play an important role in synaptic development, and learning and memory, are found throughout the brain (Monyer et al 1994;Sanz-Clemente et al 2013).…”

<i>N</i>-Linoleyltyrosine Protects against Transient Cerebral Ischemia in Gerbil <i>via</i> CB2 Receptor Involvement in PI3K/Akt Signaling Pathway

“…Although many neuroprotective agents protected against neuronal damage in cerebrovascular diseases, few neuroprotective agents are effective in vivo due to neglecting the correlation of multiple biological injuries of ischemia. [3][4][5] Therefore, it became a hot topic about novel neuroprotective agents in ischemia via intervening in multiple pathways.…”